US5621099A - Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates - Google Patents

Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates Download PDF

Info

Publication number
US5621099A
US5621099A US08/586,638 US58663896A US5621099A US 5621099 A US5621099 A US 5621099A US 58663896 A US58663896 A US 58663896A US 5621099 A US5621099 A US 5621099A
Authority
US
United States
Prior art keywords
group
compound
tert
formula
sub
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US08/586,638
Other languages
English (en)
Inventor
Hirokazu Annoura
Toshio Tatsuoka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asubio Pharma Co Ltd
Original Assignee
Suntory Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suntory Ltd filed Critical Suntory Ltd
Assigned to SUNTORY LIMITED reassignment SUNTORY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANNOURA, HIROKAZU, TATSUOKA, TOSHIO
Application granted granted Critical
Publication of US5621099A publication Critical patent/US5621099A/en
Assigned to DAIICHI SUNTORY PHARMA CO., LTD. reassignment DAIICHI SUNTORY PHARMA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SUNTORY LIMITED
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to a process of producing of hymenialdisine, its derivatives, and their salts of the formula (I): ##STR2## (wherein X 1 is a halogen atom or hydrogen atom.)
  • the present invention further relates to intermediates for producing the above compound (I) and processes for producing the same.
  • hymenialdisine has been isolated from Axinella verrucosa, Acanthella aurantiaca (Cimino, G. et al: Tetrahedron Lett., 23, 767 (1982)), Hymeniacidon aldis (Kitagawa, I. et al: Chem. Pharm. Bull., 31, 2321 (1983)), and an unconfirmed Kololevu sponge (Schmitz, F. et al: J. Nat. Prod., 48, 47 (1985)), while debromohymenialdisine has been isolated from Phakellia flabellata (Sharma, G. et al: J. Chem. Soc., Chem.
  • the compound having an X 1 of a bromine atom is hymenialdisine, while the compound having an X 1 of a hydrogen atom is debromohymenialdisine.
  • Hymenialdisine and debromohymenialdisine are known to have antineoplastic activities (Pettit, G. et al: Can. J. Chem., 68, 1621 (1990)). Furthermore, debromohymenialdisine is known to have ⁇ -adrenoceptor blocking effect (Kobayashi, J. et al: Experimentia., 44, 86 (1988)).
  • hymenialdisine and debromohymenialdisine have an inhibitory action against protein phosphokinases, in particular, protein kinase C (Nishizuka, Y.: Nature, 334, 661 (1988); idem, JAMA, 262, 1826 (1989)), which plays an important role in cellular signal transduction (Nambi, P. et al: International Disclosure W093/16703).
  • protein kinase C for example, cerebral ischemic disorders, cerebral vasospasm, ischemic cardiac diseases, high blood pressure, arteriosclerosis, inflammation, asthma, kidney disorders, rheumatoid arthritus, and sthenia of immunofunctions.
  • Hymenialdisine and debromohymenialdisine can only be obtained in minute quantities when extracted and isolated from nature, so there has been a strong demand for the development of an efficient process of production enabling economical mass production of hymenialdisine and its derivatives.
  • Such a technique has not yet been known. There has just been a few studies on conversion from aldisin. Even these have not given satisfactory results. Complete synthesis is not yet achieved (Prager, R. et al: Aust. J. Chem., 43, 367 (1990); idem, ibid. 45, 1771 (1992)).
  • the objective of the present invention is to provide a process for economically and efficiently producing of hymenialdisine and its derivatives at a mass production.
  • the other objectives of the present invention are to provide synthetic intermediates useful for the production of these compounds and a process for producting the same.
  • the present inventors succeeded in the complete chemical synthesis of hymenialdisine and its derivatives having the formula (I): ##STR3## (wherein X 1 is a halogen atom or hydrogen atom.)
  • halogen atom includes a chlorine atom, bromine atom, and iodine atom.
  • the hymenialdisine having the formula (I) and its derivatives can be synthesized by the processes shown below. These processes will be explained one after the other.
  • the compounds (IIa) and (IIb) are obtained from the known starting materials (VIII) and (XV), then the compound (IV) is obtained from these compounds (II) (step 3).
  • the compound (V) is obtained from the compound (IV) (step 4)
  • the compound (VIa) is obtained from the compound (V) (step 5).
  • the compound (VIb) is obtained from the compound (IVa) (step 6) and the compound (VII) is obtained from the compound (VI) (step 7).
  • the desired compound (I) is obtained from the resultant compound (VII) (step 8).
  • the compound (IIa) having an X 1 in formula (II) of a halogen atom can be synthesized from the known starting material pyrrole-2-carboxylic acid or its derivatives (VIII) by the following steps: ##STR4## (wherein R" is a hydrogen atom or a protective group of a carboxyl group, R 2 is a trimethylsilylethoxymethyl group, benzyloxymethyl group, p-methoxybenzyloxymethyl group, methoxymethyl group, methoxyethoxymethyl group, tert-butoxymethyl group, p-anisyloxymethyl group, guaiacolmethyl group, tert-butyldimethylsiloxymethyl group, dimethyltexylsiloxymethyl group, or tert-butyldiphenylsiloxymethyl group, R 3 is a trimethylsilylethoxymethyl group, benzyloxymethyl group, p-methoxybenzyloxymethyl group, tert-
  • the groups which can be easily replaced by an amino group for the group W of the compound (VIII) include a halogen atom, carboxylic acid residue, etc.
  • the various methods described in the "Compendium for Organic Synthesis” can be used.
  • DEPC diethyl phosphate cyanide
  • DPPA diphenyl phosphate azide
  • DCC dicyclohexylcarbodiimide
  • 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 2-iodo-1-methylpyridinium iod
  • a method for converting 2-pyrrolecarboxylic acid by an ordinary method to an acid halide, a symmetric acid anhydride, a mixed acid anhydride, a p-nitrophenyl ester, or other active ester, followed by causing a reaction, etc. may be used.
  • the resultant compound (X) is converted to (XI) by a halogenation reaction.
  • This halogenation reaction may be performed by treating the compound (X) in an inert solvent such as methylene chloride, 1,2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, or dimethylformamide at a temperature of -50° to 100° C., preferably -10° to 60° C.
  • a halogenation agent such as N-chlorosuccinimide, trichloroisocyanuric acid, tert-butyl hypochlorite, iodine trichloride, N-bromosuccinimide, bromine, dioxane-bromine complex, 2,4,6,6-tetrabromo-2,5-cyclohexadiene, N-iodosuccinimide, iodine, iodine/potassium iodide, iodine/periodic acid, iodine-morpholine complex, iodine monochloride, or iodine monochloride/zinc chloride for 1 to 12 hours.
  • a halogenation agent such as N-chlorosuccinimide, trichloroisocyanuric acid, tert-butyl hypochlorite, iodine trichloride, N-bromosuccinimide,
  • the resultant compound (XI) is treated, if necessary, by the action of an acid or base or by a suitable means such as catalytic reduction to remove the protective groups, then is subjected to a cyclization reaction.
  • the cyclization reaction is performed by treating the compound (XI) with an organic acid such as methanesulfonic acid or an inorganic acid such as sulfuric acid or polyphosphoric acid or by a mixture thereof with phosphorus pentaoxide at room temperature to 170° C., preferably 80° to 130° C.
  • a solvent which is not interfering with the reaction may be added.
  • the resultant compound (XII) may be converted into the compound (XIII) by treatment in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, benzene, toluene, or xylene in the presence of a base such as sodium hydroxide, potassium hydroxide, or potassium tert-butoxide at a temperature of -50° to 100° C., preferably -20° to 60° C., with 0.8 to 1.5 equivalents, with respect to compound (XII), of trimethylsilylethoxymethyl chloride, benzyloxymethyl chloride, p-methoxybenzyloxymethyl chloride (Kozikowski, A.
  • an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, benzene, toluene, or xylene
  • the resultant compound (XIII) may be converted into the compound (XIV) by treatment in an inert solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, benzene, toluene, or xylene at a temperature of -50° to 100° C., preferably -20° to 60° C., in the presence of a base such as sodium hydroxide, potassium hydroxide, or potassium tert-butoxide, with 0.8 to 1.5 equivalents of trimethylsilylethoxymethyl chloride, benzyloxymethyl chloride, p-methoxybenzyloxymethyl chloride, chloromethylmethyl ether, 2-methoxyethoxymethyl chloride, tert-butoxymethyl chloride, p-anisyloxymethyl chloride, guaiacolmethyl chloride, tert-butyldimethylsiloxymethyl chloride, dimethyltexylsiloxymethyl chloride
  • the resultant compound (XIV) is separated and purified by a purification method generally used, for example, column chromatography, to obtain the compound having the formula (IIa): ##STR5## (wherein R 2 and R 1 are as defined above and X 4 is a halogen atom.)
  • the compounds obtained by these reactions may be used as they are for the next processes, but if necessary, they may also be used after purification by a purification method generally used, for example, recrystallization or column chromatography.
  • the starting aldisin (XV) is a known compound described in Prager, R. et al: Aust. J. Chem., 43, p. 355 to 365 (1990). It may be prepared in the same way as the method for obtaining the compound (XIV) from the compound (XII) of the step 1.
  • the resultant compound (IIb) may be used as is for the next step, but if necessary, it may also be used after purification by a purification method generally used, for example, recrystallization or column chromatography.
  • This step may be performed by causing a reaction in an inert solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene, xylene, or dimethylformamide in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethylate, or potassium tert-butoxide at a temperature of 0° to 120° C., preferably room temperature to 70° C., with 1 to 10 equivalents, with respect to compound (II), of trimethyl phosphonoacetate, methyldiethyl phosphonoacetate, ethyldimethyl phosphonoacetate, methyldiisopropyl phosphonoacetate, ethyldiethyl phosphonoacetate, isopropyldiethyl phosphonoacetate, tert-butyldiethyl phosphonoacetate, methyl bis(2,2,
  • the compound (IV) obtained by the above method can be used as it is as a material for producing the compound (V), but when necessary it is possible to separate the compound (IVa) used in the step 6 by column chromatography for example, purify it, and then use that.
  • This step may be performed by causing a reaction in an inert solvent such as tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, or toluene in the presence of a strong base such as potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl) amide, lithium bis(trimethylsilyl)amide, or lithium diisopropylamide, at a temperature of -100° to 20° C., preferably -78° to 0° C., with 1 to 1.5 equivalents, with respect to compound (IV), of an oxidizing agent such as 2-benzenesulfonyl-3-phenyloxaziridine (Davis, F. et al: J. Org.
  • an inert solvent such as tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, or toluene
  • a strong base such as potassium bis(trimethylsilyl)amide, sodium bis(trimethyl
  • the compound (V) obtained by the above method may be used as it is as the material for producing the compound (VIa), but if necessary, it may also be used after purification by a purification method generally used, for example, column chromatography.
  • R 4 is an alkylsulfonyloxy group or arylsulfonyloxy group, preferably the alkyl group includes an alkyl group having 1 to 4 carbon atoms or a halogen substituted methyl group, preferably, as the halogen, a fluorine atom or chlorine atom, preferably the aryl group includes a phenyl group p-tolyl group, 4-methoxyphenyl group, 4-chlorophenyl group, or nitrophenyl group.
  • This step may be performed by causing a reaction in an inert solvent such as methylene chloride, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, xylene, or ethyl acetate in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate or potassium hydrogencarbonate at a temperature of -20° to 100° C., preferably -10° to 60° C., with 1 to 10 equivalents, with respect to compound (V), of a sulfonylating agent such as methanesulfonyl chloride, methanesulfonic anhydride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, 1-buta
  • the compound (VIa) obtained by the above method may be used as it is, as the material for producing the compound (VII), but if necessary, it may also be used after purification by a purification method generally used, for example, column chromatography.
  • This step may be performed by treating the compound (IVa) in an inert solvent such as methylene chloride, 1,2-dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, or dimethylformamide at -50° to 120° C., preferably -20° to 80° C., with 0.3 to 1.2 equivalents of a halogenating agent such as N-chlorosuccinimide, trichloroisocyanuric acid, tert-butyl hypochlorite, iodine trichloride, N-bromosuccinimide, bromine, dioxane-bromine complex, 2,4,6,6-tetrabromo-2,5-cyclohexadiene, N-iodosuccinimide, iodine, iodine/potassium iodide, iodine/periodic acid, i
  • the compound (VIb) obtained by the above method may be used as it is, as the material for producing the compound (VII), but if necessary, it may also be used after purification by a purification method generally used, for example, column chromatography.
  • This step may be performed by causing a reaction with the compound (VI) in an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol methyl ether, dimethylformamide, or dimethylsulfoxide at a temperature of 0° to 200° C., preferably room temperature to 120° C., with 1 to 10 equivalents of guanidine for 2 to 24 hours.
  • an inert solvent such as benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol methyl ether, dimethylformamide, or dimethylsulfoxide
  • the compound (VII) obtained by the above method may be used as it is, as the material for producing the compound (I), but if necessary it may also be used after purification by a purification method generally used, for example, recrystallization or column chromatography.
  • the Z-configuration was confirmed, for example, from the fact that the signal of the 5-position methylene proton in proton NMR shifts to the low magnetic field side due to anisotropic effect of the spatially close carbonyl group. Further, this result can be confirmed from the conversion of the compound (VII) to the compound (I).
  • This step may be performed by causing a reaction at a temperature of -50° to 150° C., preferably -20° to 120° C., of the compound (VII) with 1 to 10 equivalents of tetrabutylammonium fluoride/tetrahydrofuran, 1 to 10 equivalents of tetrabutylammonium fluoride/ethylenediamine, 1 to 10 equivalents of methanol/hydrochloric acid, 1 to 10 equivalents of ethanol/hydrochloric acid, etc.
  • this step may be performed by general deprotection methods such as a method of using an acid catalyst, the catalytic reduction method, and oxidation, for example, the various methods as described in "Protective Groups in Organic Synthesis” (T. W. Greene; John Wiley & Sons), etc.
  • the compound (I) obtained by the above method may be purified by a purification method generally used, for example, recrystallization or column chromatography.
  • an acid addition salt of the compound having the formula (I) may be produced by reacting the same by an ordinary method with an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, or phosphoric acid or an organic acid such as maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, oxalic acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid, palmitic acid, and tannic acid.
  • an inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, or phosphoric acid
  • an organic acid such as maleic acid, fumaric acid, tartaric acid, citric acid, lactic acid, oxalic acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, adipic acid
  • a 5 g amount of the mixture of the compounds (4) synthesized in Reference Example 4 was gradually added under ice cooling to a 100 ml dimethylformamide suspension of 0.87 g of sodium hydride (60% oil). The mixture was stirred at room temperature for 1 hour. A 3.7 ml amount of trimethylsilylethoxymethyl chloride was dropwise added under ice cooling, the mixture was stirred at room temperature for 2 hours, then a saturated aqueous solution of ammonium chloride was added and extraction was performed by ethyl acetate.
  • a 5 ml dimethylformamide solution of 740 mg of the compound (5) synthesized in Reference Example 5 was dropwise added under ice cooling to a 10 ml dimethylformamide suspension of 87.3 mg of sodium hydride (60% oil). The mixture was stirred at room temperature for 1 hour. A 0.39 ml amount of trimethylsilylethoxymethyl chloride was dropwise added under ice cooling, the mixture was stirred at room temperature for 2 hours, then a saturated aqueous solution of ammonium chloride was added and extraction was performed by ethyl acetate.
  • Example 2 The same procedure was followed as in Example 1 to obtain 205 mg of the above-referenced compound (11) (yield 25%) and 470 mg of the above-referenced compound (12) (yield 58%) from 700 mg of the compound (8) synthesized in Reference Example 7, 329 mg of sodium hydride (60% oil), and 1.63 ml of ethyl diethyl phosphonoacetate.
  • a 135 mg amount of the above-referenced compound (14) (yield 72%) was obtained from 182 mg of a mixture of the compound (11) and (12) synthesized in Example 2, 0.88 ml of potassium bis(trimethylsilyl)amide (0.5 mol/toluene solution), and 106 mg of 2-benzenesulfonyl-3-phenoyloxaziridine, in the same manner as in Example 3.
  • a 940 mg amount of the above-referenced compound (16) (yield 97%) was obtained from 840 mg of the compound (14) synthesized in Example 4, 0.69 mgl of triethylamine, and 0.15 ml of methanesulfonyl chloride, in the same manner as in Example 5.
  • a 420 mg amount of the above-referenced compound (19) was obtained from 935 mg of the compound (16) synthesized in Example 6 and 281 mg of guanidine to obtain the crude crystals in the same manner as in Example 8 followed by, recrystallizing from ether/methanol (yield 50%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US08/586,638 1994-05-18 1995-05-17 Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates Expired - Fee Related US5621099A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP6-104030 1994-05-18
JP10403094A JP3714685B2 (ja) 1994-05-18 1994-05-18 ハイメニアルディシン及びその誘導体並びにそれらの合成中間体の製造法並びにその合成中間体
PCT/JP1995/000941 WO1995031462A1 (fr) 1994-05-18 1995-05-17 Hymenialdisine et derive de celle-ci, procede pour produire un intermediaire servant a synthetiser ce compose, et cet intermediaire

Publications (1)

Publication Number Publication Date
US5621099A true US5621099A (en) 1997-04-15

Family

ID=14369852

Family Applications (1)

Application Number Title Priority Date Filing Date
US08/586,638 Expired - Fee Related US5621099A (en) 1994-05-18 1995-05-17 Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates

Country Status (9)

Country Link
US (1) US5621099A (fr)
EP (1) EP0711773B1 (fr)
JP (1) JP3714685B2 (fr)
KR (1) KR960703916A (fr)
AU (1) AU701436B2 (fr)
CA (1) CA2167515A1 (fr)
DE (1) DE69522642T2 (fr)
ES (1) ES2160164T3 (fr)
WO (1) WO1995031462A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999015157A2 (fr) * 1997-09-25 1999-04-01 The University Of British Columbia Inhibiteurs des points de controle g2 et dosage
US5962448A (en) * 1995-12-01 1999-10-05 Suntory Limited Pyrroloazepine derivatives
US6103899A (en) * 1993-04-08 2000-08-15 The Trustees Of Columbia University In The City Of New York Bicyclic aminoimidazoles
US6197954B1 (en) 1998-01-30 2001-03-06 The Trustees Of Columbia University In The City Of New York Intermediates for the synthesis of debromohymenialdisine and processes thereof
US6211361B1 (en) * 1999-07-20 2001-04-03 State Of Oregon Acting By And Through The Oregon State Board Of Higher Education On Behalf Of Oregon, State Univeristy Method for making debromohymenialdisine and analogs thereof
EP1106180A1 (fr) * 1999-12-08 2001-06-13 Centre National De La Recherche Scientifique (Cnrs) Utilisation de l'hymenialdisine et de ses dérivés pour la fabrication de médicaments
US20040209897A1 (en) * 2002-12-20 2004-10-21 Pharmacia Corporation Mitogen activated protein kinase-activated protein kinase-2 inhibiting compounds
US20040235820A1 (en) * 2003-05-19 2004-11-25 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US20050153955A1 (en) * 2003-05-01 2005-07-14 Irm Llc Compounds and compositions as protein kinase inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1250137B1 (fr) * 2000-01-24 2007-08-15 Genzyme Corporation Inhibiteurs du trajet de jak/stat et leur utilisation pour le traitement de l'ostéoarthrite primaire généralisée
ES2288948T3 (es) 2000-05-11 2008-02-01 Consejo Superior De Investigaciones Cientificas Inhibidores heterociclicos del glicogeno sintasa quinasa gsk-3.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206239A (en) * 1990-02-07 1993-04-27 Suntory Limited Pyrroloazepine derivatives
WO1993016703A1 (fr) * 1992-02-24 1993-09-02 Smithkline Beecham Corporation Inhibiteur de la proteine kinase c

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62161786A (ja) * 1986-01-08 1987-07-17 Mitsubishi Chem Ind Ltd ピロ−ル化合物
US4729996A (en) * 1986-05-29 1988-03-08 Harbor Branch Oceanographic Institution, Inc. Antitumor compositions and their methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5206239A (en) * 1990-02-07 1993-04-27 Suntory Limited Pyrroloazepine derivatives
WO1993016703A1 (fr) * 1992-02-24 1993-09-02 Smithkline Beecham Corporation Inhibiteur de la proteine kinase c

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
Annoura et al, "Total Syntheses of Hymenialdisine and Debromohymenialdisine: Stereospecifc Construction of the 2-Amino-4-Oxo-2-Imidazolin-5(Z)-Disubstituted Ylidene Ring System", Tetrahedron Letters, 36(3):413-416 (1995).
Annoura et al, Total Syntheses of Hymenialdisine and Debromohymenialdisine: Stereospecifc Construction of the 2 Amino 4 Oxo 2 Imidazolin 5(Z) Disubstituted Ylidene Ring System , Tetrahedron Letters , 36(3):413 416 (1995). *
Cimino et al, "Isolation and X-ray Crystal Structure of A Novel Bromo-Compound from Two Marine Sponges", Tetrahedron Letters, 23(7):767-768 (1982).
Cimino et al, Isolation and X ray Crystal Structure of A Novel Bromo Compound from Two Marine Sponges , Tetrahedron Letters , 23(7):767 768 (1982). *
Endo et al, "Pharmacologically Active Substances from Southern Pacific Marine Invertebrates", Pure & Appl. Chem., 58(3):387-394 (1986).
Endo et al, Pharmacologically Active Substances from Southern Pacific Marine Invertebrates , Pure & Appl. Chem. , 58(3):387 394 (1986). *
Kitagawa et al, "Marine Natural Products. XII.1) On the Chemical Constituents of the Okinawan Marine Sponge Hymeniacidon aldis", Chem. Pharm. Bull., 31(7):2321-2328 (1983).
Kitagawa et al, Marine Natural Products. XII. 1) On the Chemical Constituents of the Okinawan Marine Sponge Hymeniacidon aldis , Chem. Pharm. Bull. , 31(7):2321 2328 (1983). *
Kobayashi et al, "α-Adrenoceptor Blocking Action of Hymenin, a Novel Marine Alkaloid", Experientia 44, 86-87 (1988).
Kobayashi et al, Adrenoceptor Blocking Action of Hymenin, a Novel Marine Alkaloid , Experientia 44, 86 87 (1988). *
Pettit et al, "Antineoplastic Agents. 168. Isolation and Structure of Axinohydantoin1 ", Can. J. Chem., 68:1621-1624 (1990).
Pettit et al, Antineoplastic Agents. 168. Isolation and Structure of Axinohydantoin 1 , Can. J. Chem. , 68:1621 1624 (1990). *
Prager et al, "Approaches to the Synthesis of 5-Benzylidene-2-imidazolin-4-ones", Aust. J. Chem., 43:367-374 (1990).
Prager et al, "Knoevenagel Reactions of 6,7-Dihydro-pyrrolo[2,3-c]azepine-4,8(1H,5H)-dione: An Approach to the Synthesis of Pyrrolic Marine Natural Products", Aust. J. Chem., 45:1771-1777 (1992).
Prager et al, Approaches to the Synthesis of 5 Benzylidene 2 imidazolin 4 ones , Aust. J. Chem., 43:367 374 (1990). *
Prager et al, Knoevenagel Reactions of 6,7 Dihydro pyrrolo 2,3 c azepine 4,8(1H,5H) dione: An Approach to the Synthesis of Pyrrolic Marine Natural Products , Aust. J. Chem., 45:1771 1777 (1992). *
Schmitz et al, "Marine Natural Products: Pyrrololactams from Several Sponges", Journal of Natural Products, 48(1):47-53 (1985).
Schmitz et al, Marine Natural Products: Pyrrololactams from Several Sponges , Journal of Natural Products, 48(1):47 53 (1985). *
Sharma et al, "Characterizatioin of a Yellow Compound Isolated from the Marine Sponge Phakellia flabellata", J.C.S. Chem. Comm., 435-436 (1980).
Sharma et al, Characterizatioin of a Yellow Compound Isolated from the Marine Sponge Phakellia flabellata , J.C.S. Chem. Comm., 435 436 (1980). *
Y. Nishizuka, "The Family of Protein Kinase C for Signal Transduction", JAMA, 262(13):1826-1833 (1989).
Y. Nishizuka, "The Molecular Heterogeneity of Protein Kinase C and its Implications for Cellular Regulation", Nature, 334(25):661-665 (1988).
Y. Nishizuka, The Family of Protein Kinase C for Signal Transduction , JAMA , 262(13):1826 1833 (1989). *
Y. Nishizuka, The Molecular Heterogeneity of Protein Kinase C and its Implications for Cellular Regulation , Nature , 334(25):661 665 (1988). *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6218549B1 (en) 1993-04-08 2001-04-17 The Trustees Of Columbia University In The City Of New York Bicyclic aminoimidazoles
US6103899A (en) * 1993-04-08 2000-08-15 The Trustees Of Columbia University In The City Of New York Bicyclic aminoimidazoles
US5962448A (en) * 1995-12-01 1999-10-05 Suntory Limited Pyrroloazepine derivatives
WO1999015157A3 (fr) * 1997-09-25 1999-09-23 Univ British Columbia Inhibiteurs des points de controle g2 et dosage
WO1999015157A2 (fr) * 1997-09-25 1999-04-01 The University Of British Columbia Inhibiteurs des points de controle g2 et dosage
US6528646B2 (en) 1998-01-30 2003-03-04 The Trustees Of Columbia University In The City Of New York Intermediates for the synthesis of debromohymenialdisine and process thereof
US6197954B1 (en) 1998-01-30 2001-03-06 The Trustees Of Columbia University In The City Of New York Intermediates for the synthesis of debromohymenialdisine and processes thereof
US6211361B1 (en) * 1999-07-20 2001-04-03 State Of Oregon Acting By And Through The Oregon State Board Of Higher Education On Behalf Of Oregon, State Univeristy Method for making debromohymenialdisine and analogs thereof
WO2001041768A2 (fr) * 1999-12-08 2001-06-14 Centre National De La Recherche Scientifique (C.N.R.S.) Utilisation d'hymenialdisine ou de ses derives pour la fabrication de medicaments
WO2001041768A3 (fr) * 1999-12-08 2002-05-10 Centre Nat Rech Scient Utilisation d'hymenialdisine ou de ses derives pour la fabrication de medicaments
EP1106180A1 (fr) * 1999-12-08 2001-06-13 Centre National De La Recherche Scientifique (Cnrs) Utilisation de l'hymenialdisine et de ses dérivés pour la fabrication de médicaments
US7098204B2 (en) 1999-12-08 2006-08-29 C.N.R.S. Hymenialdisine or derivatives thereof in the manufacture of medicaments
US20040209897A1 (en) * 2002-12-20 2004-10-21 Pharmacia Corporation Mitogen activated protein kinase-activated protein kinase-2 inhibiting compounds
US7423031B2 (en) 2003-05-01 2008-09-09 Irm Llc Compounds and compositions as protein kinase inhibitors
US20050153955A1 (en) * 2003-05-01 2005-07-14 Irm Llc Compounds and compositions as protein kinase inhibitors
US20040235820A1 (en) * 2003-05-19 2004-11-25 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US20060287296A1 (en) * 2003-05-19 2006-12-21 Tepe Jetze J Preparation of hymenialdsine derivatives and use thereof
US20060293305A1 (en) * 2003-05-19 2006-12-28 Tepe Jetze J Preparation of hymenialdisine derivatives and use thereof
US20070049575A1 (en) * 2003-05-19 2007-03-01 Tepe Jetze J Preparation of hymenialdisine derivatives and use thereof
US7193079B1 (en) 2003-05-19 2007-03-20 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US7335769B2 (en) 2003-05-19 2008-02-26 Board Of Trustees Of Michigan State University Preparation of hymenialdsine derivatives and use thereof
US7385055B2 (en) 2003-05-19 2008-06-10 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US20060276451A1 (en) * 2003-05-19 2006-12-07 Tepe Jetze J Preparation of hymenialdisine derivatives and use thereof
US7601710B2 (en) 2003-05-19 2009-10-13 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof
US7732436B2 (en) 2003-05-19 2010-06-08 Board Of Trustees Of Michigan State University Preparation of hymenialdisine derivatives and use thereof

Also Published As

Publication number Publication date
AU2454195A (en) 1995-12-05
EP0711773B1 (fr) 2001-09-12
DE69522642D1 (de) 2001-10-18
EP0711773A1 (fr) 1996-05-15
JPH07309874A (ja) 1995-11-28
JP3714685B2 (ja) 2005-11-09
CA2167515A1 (fr) 1995-11-23
AU701436B2 (en) 1999-01-28
WO1995031462A1 (fr) 1995-11-23
DE69522642T2 (de) 2002-04-18
KR960703916A (ko) 1996-08-31
ES2160164T3 (es) 2001-11-01
EP0711773A4 (fr) 1996-06-19

Similar Documents

Publication Publication Date Title
US5874581A (en) 2-silyloxy-tetrahydrothienopyridine, salt thereof and process for preparing the same
US5621099A (en) Synthetic method of hymenialdisine and its derivatives and their synthetic intermediates, and those synthetic intermediates
JPH0813819B2 (ja) 免疫抑制活性を有するｏ−ヘテロアリール、ｏ−アルキルヘテロアリール、ｏ−アルケニルヘテロアリール及びｏ−アルキニルヘテロアリールマクロライド
US5468859A (en) Process for asymmetric total synthesis of camptothecin analogues
JPH1180131A (ja) エチニルピリミジン誘導体
US5003087A (en) Process for preparing a naphthalene derivative and a synthetic intermediate thereof
SK84494A3 (en) Benzopyrane compounds, method of their preparation, method of preparation of semifinished products, pharmaceutical agent and use of these compounds
US6071938A (en) Benzopyrans
US5990319A (en) Synthesis of bisindolylmaleimides
US6011159A (en) Processes and intermediates for preparing substituted indazole derivatives
US5214065A (en) Dc-89 derivatives
JPH10500106A (ja) 治療物質としての置換された縮合および橋かけ二環式化合物
US5763451A (en) Dynemicin analogs
US6005118A (en) Methods of preparing 4-cyano-4 (substituted indazole) cyclohexane-carboxylic acids useful as PDE4 inhibitors
JP3338854B2 (ja) 新しいアレノ〔ｅ〕インドールの製造方法
JP2002500658A (ja) ２−アミノ−７−（１−置換−２−ヒドロキシエチル）−３，５−ジヒドロピロロ［３，２−ｄ］ピリミジン−４−オン
US5852204A (en) Pyrrolo 3,2-b-!-carbazoles and 1H 1!benzothieno 2,3-f! indoles having anti-tumor activity
KR0161990B1 (ko) 4,5,6,7-테트라히드로-1H-이미다조[4,5-c]피리딘-6-카르복시산 아미드 유도체 및 이를 포함하는 안기오텐신 II(AII)에 대한 길항제
JPH0517471A (ja) フラン誘導体
JPH1036352A (ja) （１１Ｅ）−５−アミノ−１１−エチリデン−５，６，９，１０−テトラヒドロ−５，９−メタノシクロオクタ［ｂ］ピリジン−２（１Ｈ）−オン誘導体およびその製造中間体
WO1993018030A1 (fr) Derives de benzimidazole antagonistes de l'angiotensine ii
JP2004244425A (ja) ハイメニアルディシン及びその誘導体の合成中間体
US5248692A (en) DC-89 derivatives as anti-tumor agents
JPH0342276B2 (fr)
JP3857353B2 (ja) ピロロキノリン誘導体

Legal Events

Date Code Title Description
AS Assignment

Owner name: SUNTORY LIMITED, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ANNOURA, HIROKAZU;TATSUOKA, TOSHIO;REEL/FRAME:007875/0417

Effective date: 19960111

FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

FPAY Fee payment

Year of fee payment: 4

AS Assignment

Owner name: DAIICHI SUNTORY PHARMA CO., LTD., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SUNTORY LIMITED;REEL/FRAME:013868/0759

Effective date: 20030314

FPAY Fee payment

Year of fee payment: 8

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20090415